Formoterol, (+/-)N-[2-hydroxy-5-[1-hydroxy-2[[2-(p-methoxyphenyl)-2-propyl]amino]ethyl ]phenyl]-formamide, is a highly potent and .beta..sub.2 -selective adrenoceptor agonist having a long lasting bronchodilating effect when inhaled. The structure of formoterol is as shown: ##STR2##
Formoterol has two chiral centers in the molecule, each of which can exist in two possible configurations. This gives rise to four combinations: (R,R), (S,S), (R,S) and (S,R). (R,R) and (S,S) are mirror images of each other and are therefore enantiomers; (R,S) and (S,R) are similarly an enantiomeric pair. The mirror images of (R,R) and (S,S) are not, however, superimposable on (R,S) and (S,R), which are diastereomers. Formoterol is available commercially only as a racemic mixture (R,R) plus (S,S) in a 1:1 ratio, and the generic name formoterol refers to this enantiomeric mixture.
The graphic representations of racemic, ambiscalemic and scalemic or enantiomerically pure compounds used herein are taken from Maehr J. Chem. Ed. 62, 114-120 (1985): solid and broken wedges are used to denote the absolute configuration of a chiral element; wavy lines indicate disavowal of any stereochemical implication which the bond it represents could generate; solid and broken bold lines are geometric descriptors indicating the relative configuration shown but denoting racemic character; and wedge outlines and dotted or broken lines denote enantiomerically pure compounds of indeterminate absolute configuration. Thus, the formula for formoterol above reflects the racemic nature of the commercial material, while among the structures below, those having open wedges are intended to encompass both of the pure enantiomers of that pair and those having solid wedges are intended to encompass the single, pure enantiomer having the absolute stereochemistry shown.
Representation of Bonds to Chiral Carbons According to Maehr
______________________________________ Symbol Stereochemical Significance ______________________________________ ##STR3## Optically pure - Indeterminate Configuration ##STR4## Racemic - but having the relative configuration shown ##STR5## Chiral - Absolute Configuration ##STR6## No Stereochemistry Indicated ______________________________________
The synthesis of the four stereoisomers of formoterol has been reported in the literature. In one method, the (R,R)- and (S,S)- isomers were isolated by stereoselective crystallization of racemic formoterol with optically pure tartaric acid (Murase et al., Chem. Pharm. Bull. 26, 1123-1129 (1978)). In another method, racemic 4-benzyloxy-3-nitrostyrene oxide was coupled with an optically pure (R,R)- or (S,S)-N-(1-phenylethyl)-N-(1-(p-methoxyphenyl)-2-propyl)amine to give a diastereomeric mixture of formoterol precursors, which were then separated by semipreparative HPLC and transformed to the pure formoterol isomers (Trofast et al., Chirality 3, 443-450 (1991)). Both methods suffer from very low yields (&lt;2%) and long synthetic procedures. -Amino-4-hydroxy-.alpha.-[[[2-(4-methoxyphenyl)-1-methylethyl]amino]methyl ]-benzenemethanol (Chem. Abst. Reg. No. 15051-24-9) has been disclosed as an undesired side product in a synthesis of formoterol (Spanish Patent ES 2031407). Its structure is shown below. ##STR7## Neither its deliberate synthesis nor its pharmacology has been previously reported.